This invention is directed to a prolamine-plant polar lipid composition, its method of preparation and its uses for delivery of active agents, including therapeutic agents and cosmetic agents, and for wound healing, wound protection and hemostasis.
A number of different approaches are available for delivering active agents to a predetermined target site in the body. For example, formulations have been developed for systemic delivery of therapeutic agents which are provided orally and are degraded in the buccal cavity or in the bowel so as to release a therapeutic agent in a controlled manner. Alternatively, systemic delivery of therapeutic agents has been achieved by transdermal delivery using multilayered patches Patches have been designed for use in transdermal delivery or topical delivery of drugs and have also been used as wound dressings in which the presence of a therapeutic agent is optional.
Developments in formulations suitable for ingestion include polymeric coatings that slowly degrade and liberate drug over an extended period of time. Polymeric coatings may be formed from protein or carbohydrates or lipids. Examples of proteins include albumin (Ohya et al. J. Macromol. Sci. Chem. 28, (1991), 743-760); gelatin (Yan et al., Biomaterials 12, (1991), 640-644); cross linked gelatin (Digenis et al. J. Pharm. Sci. 83, (1994), 915-921); gliadin (Stella et al. International Journal of Pharmaceutics 121, (1995), 117-121; WO 96/21462; U.S. Pat. No. 5,160,732); and casein (Jayakrishnan et al. Int. J. Pharm., 106, (1994), 221-228). Examples of polysaccharides include cellulose derivatives (Ghorab et al. J. Microencapsul. 7, (1990), 447-454); and examples of lipids include ceramide (WO 96/21462). Ceramides have been used as coatings for granules, tablets, and nutritives U.S. Pat. Nos. 4,137,300, 5,160,742, 5,182,130, EP-A-O 090 559, WO-A-96/21462 and WO-A-93/12771. For example, in U.S. Pat. No. 5,160,742; the active ingredient is an antibiotic which is contained in a core and has at least one coating of prolamine and one coating of an enteric compound. Similarly, in U.S. Pat. No. 5,182,130, edible coatings are described that are formed from prolamines that are applied to an active agent contained in an aqueous microparticle. Gliadins have also been used to form capsules to deliver drugs orally. Stella et al. (1995) reported an oral drug delivery capsules in which the active agent, paracetemol, was incorporated into a capsule formed from gliadin. Stella also incorporated paracetemol in a gliadin containing chewing gum for delivery by means of mastication. Despite innovations in oral drug delivery, there exists a need for improvements in controlled release of therapeutic agents at a sustained rate over extended periods of time.
Whereas tablets and capsules are suitable only for delivery of a therapeutic agent systemically through the stomach or intestinal mucosa, transdermal delivery, which relies on the adhesion to the skin of the patch, offers a potentially more direct route of delivery to the blood. Advantages of transdermal delivery include: avoidance of first pass effects described for tablets and capsules; and problems associated with stomach irritation. In certain circumstances, it is desirable to deliver a therapeutic agent or cosmetic agent topically to the skin at a target site. Both transdermal and topical delivery devices rely on the adherence of a patch to the surface of the skin or other body surface such as the surface of nose, mouth, vagina, or rectum or wound surface.
Patch delivery devices are generally either of the drug reservoir type or alternatively contain the active agent dispersed throughout a polymer matrix. Where polymer matrices are utilized, these are generally synthetic polymers such as acrylates. However, a naturally occurring polycationic polysaccharide polymer, identified as chitosan, has been used in sustained release formulations of therapeutic agents (Thacharodi and Rao; Biomaterials 16 (1995) 145-148). Chitosan is difficult to purify and is commonly contaminated with proteins. In addition, chitosan lacks adhesive properties. Therefore, an adhesive layer formed from acrylates is laminated to the chitosan to form the interface between the body and the patch. However, the use of chitosan may be associated with adverse skin reactions. Another naturally occurring polymer that has been used in patches is protein. For example, animal collagen is a protein which has been used as an adhesive polymer. Just as with chitosan, a separate adhesive layer is recommended for the collagen laminate. (EP 0 518697A2).
Collagen has been used in wound healing applications to form pads for purposes of controlling bleeding (WO 93/10731). The collagen pads absorb wound exudate to produce a firm primary vital adhesion to the wound. EP 0 621 044 A2 reports an attempt to increase the strength of collagen sheets to avoid tearing when wet and further suggests the introduction of agents into the collagen to assist the healing process. Problems associated with the use of collagen, a biological polymer from animals, include those arising from the fact that collagen is an animal protein. These problems include possible contamination of the protein with disease-causing viruses; and stimulation of an immune response in the immunological active environment of a wound during multi-day exposure of the collagen film to the wound.
There are a number of limitations associated with existing patches. These include: irritation of the body surface associated with the patch; reversible adhesive attachment of the patch to the body surface for extended periods of time; and capacity for retaining active agents. In certain situations, it is desirable for the patch to have a large surface area such as in wound healing applications in which case, the plasticity of the patch and the lack of irritation are important desirable characteristics. There is an unmet need for biocompatible adhesive polymers for transdermal or topical delivery of drugs to body surfaces as well as for patches suitable for wound healing and hemostasis, that cause minimal irritability, have a suitable drug capacity to modulate the size of the patch, are not immunogenic and are free from contamination with pathogens. Furthermore, there is an unmet need for a moisturizing anti-irritant adhesive non-animal protein film that is biodegradable, and has the plasticity to remain intact in a moist environment. In addition, it would be desirable to obtain a film which may be suitable for wound protection and healing so as to seal moisture into a healing wound while excluding infectious agents from the air and permitting diffusion of oxygen to the wound.
The invention addresses the unmet need for a biocompatible adhesive polymer for transdermal or topical delivery of drugs to body surfaces as well as for patches suitable for wound healing and hemostasis, that cause minimal irritability, have reduced immunogenicity, and are substantially free from contamination with pathogens. Furthermore, the invention provides a film that seals moisture into a healing wound while excluding infectious agents from the air and permitting diffusion of oxygen to the wound.
In an embodiment of the invention, a composition is provided that includes a mixture of a prolamine, a plant polar lipid and at least one polyalcohol in a hydro-alcoholic solution so as to form a substantially homogeneous dispersion with skin adhesive properties. In a preferred embodiment, the prolamine is a cereal prolamine more particularly a gliadin having a w/w concentration of 20-40% where the plant polar lipid is isolated from a cereal and includes at least one of a ceramide or a glycosylceramide at a concentration greater than 50%, and a w/w concentration of 0.1%-5%, the prolamine and plant polar lipid being homogeneously dispersed in a hydro-alcoholic solution.
In an embodiment of the invention, the dispersion forms a film, where the film may be rolled into a compact form so as to be capable of insertion within a capsule. The film may include a plasticizing agent such polyalcohol for example, glycerol or sorbitol where the concentration of the polyalcohol may be as much as 80% w/w (dry weight).
In an embodiment of the invention, an active agent is contained within the prolamine-plant polar lipid-polyalcohol dispersion where the active agent may be a therapeutic agent or a cosmetic agent for topical or systemic delivery. The method may direct the active agent to the target site via oral, buccal, rectal, vaginal or topical routes. The homogeneous dispersion may be aerosolized, the aerosol capable of forming a film on the body surface.
In an additional embodiment of the invention, a method for forming a gel is provided that includes the steps of selecting a prolamine and a plant polar lipid; and mixing the prolamine and the plant polar lipid at an effective temperature and for an effective time in a hydroalcohol solvent so as to form a substantially homogeneous dispersion, the dispersion forming a gel. In preferred embodiments, the effective temperature is in the range of 40-50xc2x0 C. and the time is least 10 minutes
In an embodiment of the invention, a method is provided for delivering an active agent to a target site, that includes forming a homogeneous dispersion of a prolamine, a plant polar lipid and at least one polyalcohol in a hydro-alcoholic solution; adding at least one active agent to the dispersion; permitting the dispersion to form a skin adhesive gel; and applying the gel to the skin so as to deliver the active agent to the target site. In further embodiments, the target site may be systemic or topical and the active agent selected from the group comprising: local and systemic pain relievers, anti-arthritis agents; buccally active agents, agents for enhancing dental hygiene, agents for enhancing mouth hygiene, antimicrobials agents, anesthetic agents, keratolytic agent; wound healing agents; antipyretics; anti-inflammatory agents, antispasmodics, sympathomimetic drugs, antiparasitic agents, hypoglycemic drugs, nutritional agents, cardiovascular agents, agents for smoking cessation, vitamins, hemostatic agents, skin growth agents. The active agent may further be selected from the group comprising: agents for improving skin appearance, topically active agents for treating dermal and nail diseases; anti-hyperpigmentation, anti-blotching, anti-aging, eye contour, slimming, anti-cellulite, soothing/sunburn anti-irritating, skin firming and lifting, anti-elastase and anti-collagenase agents, free radical scavengers, seboregulators, hydratives, and AHA (xcex1-hydroxy acids) specific products.
A further embodiment of the invention is a method for protecting a wound, that includes the steps of forming a homogeneous dispersion of a prolamine, a plant polar lipid and at least one polyalcohol in a hydro-alcoholic solution; permitting the dispersion to form a skin adhesive gel; and applying the gel to the skin so as to provide protection to the wound. The method may further include adding an oxidizing agent to the dispersion where the oxidising agent may be vitamin E.